Method for preventing and treating peripheral neuropathy by administering selegiline

ABSTRACT

The present invention is directed to methods for alleviating the symptoms associated with peripheral neuropathy. The neuropathy may be the result of a genetically inherited condition, systemic disease or exposure to a toxic agent. A reduction or elimination of symptoms is obtained by administering the drug selegiline. The invention is also directed to a method for treating patients with cancer by administering a chemotherapeutic agent known to have a toxic affect on peripheral nerves together with selegiline.

FIELD OF THE INVENTION

[0001] The present invention relates to a medical treatment forpreventing or alleviating the symptoms associated with peripheralneuropathy caused by disease or exposure to a toxic agent, e.g., achemotherapeutic cytotoxic agent. A reduction or elimination of symptomsis accomplished by administering the drug selegiline.

BACKGROUND OF THE INVENTION

[0002] Peripheral neuropathy is associated with a wide variety ofcauses, including genetically acquired conditions, systemic disease orexposure to toxic agents. It can manifest itself as a dysfunction ofmotor, sensory, sensorimotor or autonomic nerves.

[0003] Among the most important toxic agents causing peripheralneuropathy are therapeutic agents, particularly those used for thetreatment of neoplastic disease. In certain cases, peripheral neuropathyis a major complication of cancer treatment and is the main factorlimiting the dosage of chemotherapeutic that can be administered to apatient (Macdonald, Neurologic Clinics 9:955-967 (1991)). This is truefor the commonly administered agents cisplatin, paclitaxel andvincristine (Broun, et al., Am. J. Clin. Oncol. 16:18-21 (1993);Macdonald, Neurologic Clinics 9:955-967 (1991); Casey, et al., Brain96:69-86 (1973)). The identification of methods for preventing oralleviating dose-limiting peripheral neuropathologic side effects wouldallow higher, and more therapeutically effective doses of thesechemotherapeutics to be administered to patients, i.e., the therapeuticefficacy of such chemotherapeutics is typically a function of dose andtherefore, increasing dosage provides increased patient survival(Macdonald, Neurologic Clinics 9:955-967 (1991); Oxols, Seminars inOncology 16, suppl. 6:22-30 (1989)).

[0004] Beyond the potential for increasing the effectiveness of cancerchemotherapy, the identification of new methods for treating peripheralneuropathy has obvious value in alleviating the suffering of patientswith a wide variety of systemic diseases and genetic conditions. In manycases, progressive neuropathy in the peripheral nervous system can bedebilitating or fatal.

[0005] Although selegiline has been used extensively as a treatment forParkinson's disease, its effectiveness in the prevention or treatment ofperipheral nerve dysfunction caused by toxic agents has not beenpreviously known. The present invention is directed to methods whichrely upon this surprising and unexpected discovery to reduce oreliminate symptoms associated with peripheral nerve dysfunction.

RELATED ART

[0006] Selegiline is a potent and selective irreversible inhibitor ofmonoamine oxidase B (MAO-B) and has been reported to have an action inprotecting or rescuing neurons of the central nervous system. Forexample, in a rat optic nerve crush model, selegiline has been reportedto increase the survival of retinal ganglion cells that are at risk ofundergoing apoptosis (Buys, et al., Invest. Opthalmol. Vis. Sci. 35:1484(1994)). Selegiline has also been shown to have a neuroprotective effectin a model of axotomy-induced cell death in spinal motor neurons of therat (Iwasaki, et al., J. Neurol. Sci. 125:11-13 (1994)) and to enhanceneurite outgrowth in a cultured spinal cord neuron (Iwasaki, et al.,Annals of Neurology 36:282-283 (1994)). In addition, selegiline has beenreported to increase the survival of CNS neurons after exposure tovarious chemical toxins such as MPP⁺, kainic acid, or DSP-4 (Gelowitz,et al., Soc. Neurosci. Abstr. 20:246 (1994); Tatton, et al., J.Neurosci. Res. 31:394-400 (1992); Yu, et al., J. Neurochem. 63:1820-1828(1994)).

[0007] With respect to peripheral nerves, selegiline has been reportedto be capable of rescuing axotomized rat facial motor neurons (Salo, etal., J. Neurosci. Res. 31:394400 (1992)). A recently issued patent alsosuggests that it may be used in stimulating muscle reinnervation intraumatic and non-traumatic peripheral nerve damage (U.S. Pat. No.5,444,095).

SUMMARY OF THE INVENTION

[0008] The present invention is based upon the discovery that selegilinecan be used to prevent or alleviate the symptoms associated withperipheral neuropathy. In particular, the invention provides a methodfor protecting a patient from, or treating a patient for, peripheralneuropathy caused by a toxic agent by administering selegiline in anamount sufficient to reduce or eliminate one or more of the symptomsassociated with the neuropathy. Typically, the patient will be a humanand the toxic agent will be a chemotherapeutic agent, e.g., an agentadministered for the treatment of cancer. Although the method iseffective for any toxic chemotherapeutic agent causing dysfunction ofperipheral nerves, it is most effective for those agents withparticularly severe neuropathic side effects such as cisplatin,paclitaxel, vincristine and vinblastin

[0009] Any route of delivery may be used for administering the drug, butpreferred routes avoid absorption of selegiline from thegastrointestinal tract. Thus, administration transdermally, buccally, orsublingually are among the preferred methods of delivery. The preferrednon-oral dose of selegiline is between 0.01 mg/kg per day and 0.15 mg/kgper day, based upon the weight of the free amine. When the oral route ofdelivery is used, the preferred dosage range is between 0.15 mg/kg perday and 0.75 mg/kg per day based upon the weight of the free amine(typically between about 10 and 50 mg per day).

[0010] The present invention is also directed to a method for treating apatient for peripheral neuropathy caused by a genetically inheritedcondition or systemic disease by administering selegiline in an amountsufficient to reduce or eliminate one or more of the symptoms associatedwith the neuropathy. As in the case where peripheral neuropathy is dueto exposure to a toxic agent, it is preferred that selegiline beadministered by a route that avoids absorption of the drug from thegastrointestinal tract. Transdermal, buccal and sublingual routes ofadministration are among the routes preferred. Again, the dosage ofselegiline for non-oral routes of administration should be between 0.01mg/kg per day and 0.15 mg/kg per day and, when given orally, thepreferred dosage range is between 0.15 mg/kg per day and 0.75 mg/kg perday.

[0011] The present invention is also directed to a method for treating apatient with cancer by: a) administering a chemotherapeutic agent knownto have a toxic effect on peripheral nerves at a dose effective atslowing the progression of the patient's cancer; b) concurrentlyadministering selegiline to the patient at a dose effective atpreventing, reducing or eliminating the peripheral neuropathy associatedwith the chemotherapeutic agent; and c) increasing the individual orcumulative dosage of chemotherapeutic agent until peripheral neuropathybecomes unacceptably severe. Individual dosage refers to the amount ofchemotherapeutic given at a single time, e.g. in a single infusion orinjection, whereas cumulative dosage is the total amount of achemotherapeutic administered over the full course of therapy. Thus,cumulative dosage may be increased by increasing individual dosages,extending the period of therapy or both increasing individual dosagesand extending the length of therapy.

[0012] The present invention provides the following:

[0013] In a method for maximizing the individual or cumulative dose ofan anti-neoplastic agent used in the treatment of a patient sufferingfrom a cancer that exhibits a dose-dependent response to said agent, theimprovement that comprises the concurrent administration of a selegilinecompound in an amount sufficient to permit the individual or cumulativedose of said agent to be maximized without unacceptably severeneurotoxic side effects.

[0014] As used herein “concurrent” administration of selegiline andchemotherapeutic means that the drugs are given sufficiently close intime so that their therapeutic effects overlap. The term “unacceptablysevere” refers to side effects that the patient finds intolerable orwhich the patient's physician judges to reflect neuropathy that poses soserious a threat to the patient's health that the dosage ofchemotherapeutic agent must be reduced or terminated. Typically, thepatient will be a human. The preferred chemotherapeutic agents arecisplatin, paclitaxel, vincristine and vinblastine.

[0015] As with the methods discussed previously, selegiline may beadministered by any route, but routes that avoid absorption across thegastrointestinal tract, e.g., transdermal, buccal and sublingual routes,are generally preferred. The non-oral dosage of selegiline administeredin conjunction with chemotherapeutic agent should, preferably, bebetween 0.01 mg/kg per day and 0.15 mg/kg per day based upon the weightof the free amine. In general, patients administered selegiline orallyshould receive a dose of between 0.15 mg/kg per day and 0.75 mg/kg perday.

DETAILED DESCRIPTION OF THE INVENTION

[0016] In the following description, reference will be made to variousmethodologies well known to those skilled in the art of medicine andpharmacology. Such methodologies are described in standard referenceworks setting forth the general principles of these disciplines.

[0017] A. Definitions

[0018] Peripheral neuropathy: As used herein, the term “peripheralneuropathy” refers to abnormal function or pathological changes innerves located outside of the brain or spinal column. The nerves may besensory, motor, sensorimotor or autonomic and dysfunction may manifestitself in any of the various symptoms discussed herein.

[0019] Toxic agent: For the purposes of the present invention, the term“toxic agent” is defined as any substance that, through its chemicalaction, impairs the normal function of one or more components of theperipheral nervous system. The definition includes agents that areairborne, ingested as a contaminant of food or drugs, or takendeliberately as part of a therapeutic regime.

[0020] Selegiline: Selegiline, also known asR-(−)-N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, L-(−)-deprenyl, orR-(−)deprenyl, has the following structural formula:

[0021] Unless otherwise specified, the term “selegiline,” as used hereinincludes both the free base and pharmacologically acceptable salts ofselegiline.

[0022] B. Symptoms of Peripheral Neuropathy

[0023] The present invention is directed to the prevention or treatmentof peripheral neuropathy using selegiline. The neuropathy may begenetically acquired, developed as the result of systemic illness, ordue to the exposure of a patient to a toxic agent. The treatmentobjective is to prevent, reduce or eliminate the symptoms associatedwith peripheral nerve dysfunction.

[0024] Symptoms vary widely depending upon the cause of the peripheralnerve damage and the particular types of nerves affected. Dysfunction ofperipheral sensory neurons typically manifests itself as a loss ofsensation in the limbs or elsewhere. For example, there may be numbnessin the fingers, toes or elsewhere. Clinically, a physician may evaluatesuch loss by testing the ability of a patient to sense pain, vibration,or temperature or by using nerve conductance studies.

[0025] Dysfunction in peripheral motor neurons typically manifestsitself as a clumsiness in performing physical tasks or as muscularweakness. For example, a patient may experience difficulty in buttoninga shirt or combing their hair. Muscular weakness may cause patients tobecome exhausted after relatively minor exertion and, in some cases, maycreate a difficulty in standing or walking. Clinically, a physician maydiagnosis dysfunction in motor neurons using electrophysiological testsor by direct evaluation of patient strength or dexterity. Peripheralmotor neuron dysfunction may also be diagnosed on the basis of anattenuation or absence of a neuromuscular reflex, e.g., as an absence ofthe ankle jerk reflex.

[0026] Dysfunction of peripheral autonomic nerves may lead a patient toexperience constipation or cardiac irregularities or toxicities. It isoften seen clinically as an attenuation of the postural hypotensivereflex.

[0027] C. Diseases and Toxic Agents Causing Peripheral Neuropathy

[0028] The particular systemic disease, hereditary condition or toxicagent responsible for peripheral neuropathy is not critical to theinvention. Thus, selegiline is effective for neuropathies associatedwith systemic diseases such as: uremia; childhood cholestatic liverdisease; chronic respiratory insufficiency; alcoholic polyneuropathy;multiple organ failure; sepsis; hypo-albuminemia; eosinophilia-myalgiasyndrome; hepatitis; porphyria; hypoglycemia; vitamin deficiency;chronic liver disease; primary biliary cirrhosis; hyperlipidemia;leprosy; Lyme disease; herpes zoster; Guillain-Barre syndrome; chronicinflammatory demyelinating polyradiculoneuropathy; sensory perineuritis;acquired immunodeficiency syndrome (AIDS)-associated neuropathy;Sjogren's syndrome; primary vasculitis (such as polyarteritis nodosa);allergic granulomatous angiitis; hypersensitivity angiitis; Wegener'sgranulomatosis; rheumatoid arthritis; systemic lupus erythematosis;mixed connective tissue disease; scleroderma; sarcoidosis; vasculitis;systemic vasculitides; acute tunnel syndrome; pandysautonomia; primary,secondary, localized or familial systemic amyloidosis; hypothyroidism;chronic obstructive pulmonary disease; acromegaly; malabsorption (sprue,celiac disease); carcinomas (sensory, sensorimotor, late anddemyelinating); lymphoma (including Hodgkin's), polycythemia vera;multiple myeloma (lytic type, osteosclerotic, or solitary plasmacytoma);benign monoclonal gammopathy; macroglobulinemia; cryoglobulinemia;tropical myeloneuropathies; herpes simplex infection; cytomegalovirusinfection; and diabetes.

[0029] Genetically acquired neuropathies suitable for treatment byselegiline include, without limitation: peroneal muscular atrophy(Charcot-Marie-Tooth Disease) hereditary amyloid neuropathies,hereditary sensory neuropathy (type I and type II), porphyricneuropathy, hereditary liability to pressure palsy, Fabry's Disease,adrenomyeloneuropathy, Riley-Day Syndrome, Dejerine-Sottas neuropathy(hereditary motor-sensory neuropathy-III), Refsum's disease,ataxia-telangiectasia, hereditary tyrosinemia, anaphalipoproteinemia,abetalipoproteinemia, giant axonal neuropathy, metachromaticleukodystrophy, globoid cell leukodystrophy, and Friedrich's ataxia.

[0030] A very large number of toxic agents have been described thatcause peripheral neuropathy amenable to treatment by the presentinvention. The list includes, but is not limited to, acetazolamide,acrylamide, adriamycin, alcohol, almitrine, amiodarone, amphotericin,arsenic, aurothioglucose, carbamates, carbon disulfide, carboplatin,chloramphenicol, chloroquine, cholestyramine, cisplatin, clioquinol,colestipol, colchicine, colistin, cycloserine, cytarabine, dapsone,dideoxycytidine, dideoxyinosine, dideoxythymidine, disulfiram,doxorubicin, ethambutol, ethionamide, glutethimide, gold, hexacarbons,hormonal contraceptives, hexamethylolmelamine, hydralazine,hydroxychloroquine, imipramine, indomethacin, inorganic lead, inorganicmercury, isoniazid, lithium, methylmercury, metformin, methylbromide,methylhydrazine, metronidazole, misonidazole, nitrofurantoin, nitrogenmustard, nitrous oxide, organophosphates, ospolot, penicillin,perhexiline, perhexiline maleate, phenytoin, platinum, polychlorinatedbiphenyls, primidone, procarbazine, pyridoxine, sodium cyanate,streptomycin, sulphonamides, suramin, tamoxifen, paclitaxel,thalidomide, thallium, triamterene, trimethyltin, L-tryptophan, vacor,vindesine, megadoses of vitamin A, megadoses of vitamin D, andzimeldine.

[0031] Although the particular disease or toxic agent causing peripheralnerve damage is not critical, the present invention will be particularlyvaluable in the treatment of peripheral neuropathy resulting from theadministration of chemotherapeutic agents to cancer patients. Among thechemotherapeutics known to cause peripheral neuropathy are vincristine,vinblastine, cisplatin, paclitaxel, procarbazine, dideoxyinosine,cytarabine, alpha interferon, and 5-fluorouracil (see Macdonald,Neurologic Clinics 9: 955-967 (1991)).

[0032] D. Method of Preventing or Treating Peripheral Neuropathy by theAdministration of Selegiline

[0033] Dosage

[0034] The total daily dosage of selegiline administered to a patient,typically a human patient, should be at least the amount required tominimize, reduce or eliminate one or more of the symptoms associatedwith peripheral neuropathy, typically one of the symptoms discussedabove. Ordinarily, the attending physician will administer an initialdaily non-oral dose of at least about 0.01 mg per kg of body weight,calculated on the basis of the free secondary amine, with progressivelyhigher doses being employed depending upon the response to therapy. Thefinal daily dose will be between about 0.05 mg/kg of body weight andabout 0.15 mg/kg of body weight (all such doses again being calculatedon the basis of the free secondary amine).

[0035] These are simply guidelines since the actual dose must becarefully selected and titrated by the attending physician based uponclinical conditions. The optimal daily dose will be determined bymethods known in the art and will be influenced by factors such as theage of the patient, the condition or disease associated with theperipheral neuropathy, the severity of both the neuropathy and thedisease, the condition of the patient to whom treatment is being given,the desired degree of therapeutic response, and the concomitanttherapies being administered. Dosages may be provided in either a singleor multiple dosage regimen

[0036] Dosage Forms and Route of Administration

[0037] Any route of administration and dosage form is compatible withthe present invention and there are numerous references that provideguidance in this respect. For example, U.S. Pat. No. 4,812,481 disclosesthe use of concomitant selegiline-amantadine therapy in which selegilineis used with amantadine in oral, peroral, internal, pulmonary, rectal,nasal, vaginal, lingual, intravenous, intraarterial, intracardial,intramuscular, intraperitoneal, intracutaneous, and subcutaneousformulations. U.S. Pat. No. 5,192,550 describes a dosage form forselegiline comprising an outer wall with one or more pores, in which thewall is impermeable to selegiline but permeable to external fluids. Thisdosage form may have applicability for oral, sublingual, or buccaladministration. Similarly, U.S. Pat. No. 5,387,615 discloses a varietyof selegiline compositions, including tablets, pills, capsules, powders,aerosols, suppositories, skin patches, parenterals, and oral liquids,include oil aqueous suspensions, solutions, and emulsions. Furtherdisclosed therein are selegiline-containing sustained release (longacting) formulations and devices.

[0038] Although any route of administration is compatible with thepresent invention, those that avoid the absorption of selegiline fromthe gastrointestinal tract are generally preferred. Thus, preferredroutes include parenteral, transdermal, buccal, intraocular andsublingual administration. Parenteral compositions containing selegilinemay be prepared according to conventional techniques. For example,sterile isotonic saline may be used in preparations designed forintramuscular, intravenous, intrathecal or intraarterial delivery.Sterile isotonic solutions can also be employed for intraocularadministration.

[0039] Transdermal dosage unit forms can be prepared utilizing a varietyof techniques that have been described in the art. For example, in U.S.Pat. Nos. 4,861,800; 4,868,218; 5,128,145; 5,190,763; and 5,242,950; andin the foreign patent documents EP-A 404807; EP-A 509761; and EP-A593807. A monolithic patch structure can be utilized in which selegilineis directly incorporated into the adhesive and this mixture is cast onto a backing sheet. Alternatively, selegiline as an acid addition saltcan be incorporated into a multi layer patch which effects a conversionof the salt to selegiline-free base, as described for example in EP-A593807. One can also employ a device using a lyotropic liquidcrystalline composition in which, for example, 5-15% of selegiline iscombined with a mixture of liquid and sold polyethylene glycols, apolymer, and a non-ionic surfactant, optionally with the addition ofpropylene glycol and an emulsifying agent. For further details on thepreparation of such transdermal formulations, reference can be made toEP-A 5509761.

[0040] Buccal and sublingual dosage forms of selegiline may be preparedutilizing techniques described in, for example, U.S. Pat. Nos.5,192,550; 5,221,536; 5,266,332; 5,057,321; 5,446,070; 4,826,875;5,304,379; or 5,354,885.

[0041] Form of Selegiline

[0042] The present invention is not limited to a particular form ofselegiline and the drug may be used either as a free base or as apharmaceutically acceptable acid addition salt. In the latter case, thehydrochloride salt is generally preferred. However, other salts usefulin the invention include those derived from organic and inorganic acidssuch as, without limitation, hydrobromic acid, phosphoric acid, sulfuricacid, methane sulfonic acid, acetic acid, tartaric acid, lactic acid,succinic acid, citric acid, malic acid, maleic acid, aconitic acid,salicylic acid, thalic acid, embonic acid, enanthic acid, and the like.

[0043] Manner of Treatment

[0044] The methods disclosed herein may be used for both human andnon-human subjects. With regard to the latter, the methods areparticularly, but not exclusively, directed to domesticated mammals suchas canine and feline species.

[0045] Treatment by the administration of selegiline should be continueduntil the symptoms associated with peripheral neuropathy subside. Thedrug may be either administered at regular intervals (e.g., twice a day)or delivered in an essentially continuous manner, e.g., via atransdermal patch. Patients should be regularly evaluated by physicians,e.g. once a week, to determine whether there has been an improvement insymptoms and whether the dosage of selegiline needs to be adjusted.Since delayed progressive neuropathy has been demonstrated after thecessation of cisplatin therapy (see e.g. Grunberg et al., CancerChemother. Pharmacol. 25:62-64 (1989)), it is preferred thatadministration of selegiline be continued for a period (e.g. from about1-12 months) after the end of chemotherapy.

[0046] E. Method of Treating Cancer Patients Using a Combination ofSelegiline and Chemotherapeutic

[0047] The present invention is also directed to a method for treatingcancer patients using a combination of chemotherapeutic agent andselegiline. Except as noted below, the same considerations discussed inthe sections above apply equally to the situation in which selegiline isused as part of a therapeutic regime for such patients.

[0048] Chemotherapeutic Agents

[0049] Selegiline may be used in combination with any chemotherapeuticagent that causes peripheral neuropathy as a side effect. However,treatment is especially preferred for chemotherapeutic agents that areso toxic that their dosage is limited by the peripheral neuropathy whichthey cause. Included in this group are paclitaxel, cisplatin,vincristine and vinblastine. By preventing or reducing the peripheralneuropathy associated with these agents, selegiline allows higherindividual doses to be administered to patients, thereby increasing theoverall efficacy of the therapy. In addition, the administration ofselegiline allows patients to receive a higher cumulative dose ofchemotherapeutic agent. Increased cumulative dose may result from higherdoses of agent being administered at each therapeutic cycle, an increasein the number of cycles, or a combination of higher doses and morecycles.

[0050] The most preferred chemotherapeutic agents for use in the presentinvention are cisplatin and paclitaxel, both of which have severetoxicity for peripheral nerves limiting their upper dosages (seeMacdonald, Neurologic Clinics 9: 955-967 (1991)). Although doseintensity of these agents is an important factor in achieving optimaltherapeutic results, doses substantially above about 100-120 mg/m² forcisplatin (Ozols, Seminars in Oncology 16: 22-30 (1989)) and about 175mg/m²-225 mg/m² for paclitaxel (Gianni, et al., J. Nat'l Cancer Inst.87:1169-75 (1995)), typically cannot be given.

[0051] The symptoms associated with peripheral neuropathy caused by theadministration of cisplatin include sensory polyneuropathy withparesthesias, vibratory and proprioceptive loss, loss of pin andtemperature sensation, and reduced deep tendon reflexes (see Macdonald,Neurologic Clinics 9:955-967 (1991); Ozols, Seminars in Oncology 16,suppl. 6:22-30 (1989)). Symptoms associated with other agents such asvincristine and paclitaxel include loss of deep tendon reflex responseat the ankle which may progress to complete areflexia, distal symmetricsensory loss, motor weakness, foot drop, muscle atrophy, constipation,ileus, urinary retention, impotence, and postural hypotension (Id.;Casey, et al., Brain 96: 69-86 (1973)). For the purposes of the presentinvention, the severity of these symptoms is considered to beunacceptable when either a patient judges them to be intolerable or thepatient's physician judges them to pose so serious a threat to thepatient's health that the dosage of chemotherapeutic agent must bereduced or discontinued.

[0052] Dosage Forms and Routes of Administration

[0053] The particular route of administration that is most preferredwill be determined by clinical considerations and may include any of theroutes of delivery or dosage forms discussed above. Routes ofadministration which avoid gastrointestinal absorption will often bepreferred in that these are believed to reduce the concentration ofundesirable metabolic products of selegiline generated in vivo. Thus,preferred routes will typically include transdermal, parenteral,sublingual and buccal administration.

[0054] Dosage and Manner of Treatment

[0055] In some instances, patients administered selegiline according tothe invention, will already have been on chemotherapy at the time thatselegiline treatment is initiated. As a result, an upper limit on dosageof chemotherapeutic may already have been established, beyond which thepatient experiences unacceptably severe peripheral neuropathy. In thesecases, administration of the chemotherapeutic agent should be maintainedand treatment with selegiline initiated at a non-oral dose of between0.01 mg/kg of body weight per day and 0.15 mg/kg per day. The exact timeat which chemotherapeutic and selegiline are given relative to oneanother is not critical to the invention provided that their therapeuticeffects overlap. For example, it is not essential that chemotherapeuticand selegiline be administered in a single dosage form or within an houror two of one another.

[0056] In instances in which a patient is taking multiple drugs or inwhich there is some reason to believe that they may be unusuallysensitive to selegiline, it may be desirable to start with a low initialdose (e.g., 0.01 mg/kg) in order to ensure that the patient is able totolerate the medication. Once this is established, the dosage may beadjusted upward with the preferred final dosage for non-oral routes ofadministration being approximately in the range of 0.05 to 0.15 mg/kgper day. When given orally, patients should typically receive a totaldaily dose of between 0.15 mg/kg per day and 0.75 mg/kg per day dividedinto several doses. For example, a patient may receive a dose of 5 mgorally, twice a day.

[0057] The effect of selegiline on the symptoms of peripheral neuropathyshould be evaluated by the patient over a period of time and by thepatient's physician on a regular basis (e.g., once a week). If theresults reveal that symptoms have not subsided, the daily dosage ofnon-oral selegiline may be increased up to a limit of about 0.15 mg/kg.Once a concentration of selegiline is established which is effective atreducing symptoms, the dosage of chemotherapeutic is increased until anew upper limit is established, i.e. until a dosage is established whichcannot be exceeded without causing unacceptable side effects. Theadministration of selegiline should be continued for a period of timeafter the administration of chemotherapeutic has ceased in order toprevent delayed progressive neuropathy. For example, the patient maycontinue to receive selegiline for a month or more after the end ofchemotherapy.

[0058] The same basic procedure described above can be used for patientsbeginning chemotherapy. In these cases, both the dosage ofchemotherapeutic agent and selegiline will have to be established. Thepreferred procedure is to begin by pretreating patients with selegilinebefore the administration of chemotherapeutic is begun. For example, apatient may be given 10 mg of selegiline per day for a period of oneweek before treatment with chemotherapeutic is initiated. The dosages ofboth chemotherapeutic and selegiline are then optimized as describedabove. Again, selegiline administration should be continued after theadministration of chemotherapeutic has stopped.

[0059] The examples below are for illustrative purposes only and are notintended to limit the scope of the invention.

EXAMPLE 1

[0060] Treatment of Peripheral Neuropathy Caused by Vincristine

[0061] A patient with endometrial carcinoma is given an intravenousbolus injection of vincristine at a dose of 1.4 mg/m² weekly. The toxiceffects of vincristine cause sensory loss in the fingers and toes, aloss of the ankle jerk reflex, weakness and postural hypotension. Thepatient is administered 5 mg of selegiline hydrochloride orally twice aday, once with breakfast and once at lunch. During this time, therapywith vincristine is continued and evaluations of both tumor response andtoxic side effects are carried out by a physician on a weekly basis.After continued therapy, symptoms associated with peripheral neuropathysubside. At this point, the dosage of vincristine is increased to 1.8mg/m² and the process is continued. If symptoms of peripheral neuropathydo not return at the end of another cycle of chemotherapy, dosage isincreased again until an upper limit is reached. After the final dose ofvincristin is given, selegiline administration is maintained for aperiod of one month.

EXAMPLE 2

[0062] Administration of Selegiline in Combination With Cisplatin

[0063] A patient with ovarian cancer is given weekly injections ofcisplatin at a dosage of 120 mg/m². Concurrently, the patient is givenan oral dose of 5 mg of selegiline hydrochloride twice a day. At the endof one week, the patient is evaluated for signs of peripheralneuropathy. If no symptoms appear, the dose of selegiline is maintainedand the dosage of cisplatin is increased to 140 mg/m² per week. Thisprocess is continued until an upper limit of cisplatin is identified.The effect of the therapy on tumor progression is evaluated to determinethe efficacy of the treatment.

EXAMPLE 3

[0064] Treatment of Peripheral Neuropathy Caused by Paclitaxel

[0065] A patient with breast cancer is administered selegiline orally(10 mg per day) for a period of one week. At the end of this time,treatment with paclitaxel is begun by infusing the drug intravenously ata dose of 175 mg/m¹ over a period of 3 hours. Treatment is repeatedevery 3 weeks for a total of ten cycles, with the dosage of paclitaxelbeing increased by 25 mg/m² at each cycle. During this time, treatmentwith selegiline is continued and evaluations of both tumor response andtoxic side effects are carried out by a physician on a weekly basis.Dosage of paclitaxel continues to be increased until side effects becomeunacceptably severe. Administration of selegiline is continued for onemonth after treatment with paclitaxel ends.

EXAMPLE 4

[0066] Alternative Therapeutic Regime Using Paclitaxel and Selegiline

[0067] A patient with breast cancer is administered selegiline via atransdermal patch at a dose of about 0.10 mg/kg per day for a period ofone week. At the end of this time, treatment with paclitaxel is begun byinfusing the drug intravenously at a dose of 175 mg/m² over a period of3 hours. Paclitaxel infusion is repeated every 3 weeks. During thistime, treatment with selegiline is continued and evaluations of bothtumor response and toxic side effects are carried out by a physician ona weekly basis. If peripheral neuropathy becomes unacceptably severe thedosage of selegiline is increased to about 0.15 mg/kg per day. Ifunacceptable side effects persist, the dosage of paclitaxel is reducedto 125 mg/m². Treatment cycles are continued for a period extending aslong as a beneficial effect on tumor progression is obtained or untilunacceptable side effects can no longer be eliminated. Administration ofselegiline is continued for one month after treatment with paclitaxelends.

[0068] All references cited herein are fully incorporated by reference.Having now fully described the invention, it will be understood by oneof skill in the art that the invention may be performed within a wideand equivalent range of conditions, parameters and the like, withouteffecting the spirit or scope of the invention or any embodimentthereof.

What is claimed is:
 1. A method of preventing or treating peripheralneuropathy caused by a toxic agent in a patient in need of suchprevention or treatment, said method comprising: administeringselegiline to said patient in an amount sufficient to prevent, reduce oreliminate one or more of the symptoms associated with said peripheralneuropathy.
 2. The method of claim 1, wherein said patient is a human.3. The method of claim 1, wherein said agent is a chemotherapeuticagent.
 4. The method of claim 3, wherein said chemotherapeutic agent isadministered for the treatment of cancer.
 5. The method of claim 4,wherein said agent is selected from the group consisting of cisplatin,paclitaxel, vincristine and vinblastin.
 6. The method of claim 1,wherein said selegiline is administered by a route that avoidsabsorption of selegiline from the gastrointestinal tract.
 7. The methodof claim 6, wherein said selegiline is administered transdermally,buccally or sublingually.
 8. The method of claim 6, wherein saidselegiline is administered at a dose of between 0.01 mg/kg per day and0.15 mg/kg per day based upon the weight of the free amine.
 9. A methodof treating a patient for peripheral neuropathy caused by a geneticallyinherited condition or systemic disease, said method comprising:administering selegiline to said patient in an amount sufficient toreduce or eliminate one or more of the symptoms associated with saidperipheral neuropathy.
 10. The method of claim 9, wherein said patientis a human.
 11. The method of claim 9, wherein said selegiline isadministered by a route that avoids absorption of selegiline from thegastrointestinal tract
 12. The method of claim 11, wherein saidselegiline is administered transdermally, buccally or sublingually. 13.The method of claim 11, wherein said selegiline is administered at adose of between 0.01 mg/kg per day and 0.15 mg/kg per day.
 14. In amethod for maximizing either the individual or cumulative dose of ananti-neoplastic agent used in the treatment of a patient suffering froma cancer that exhibits a dose-dependent response to said agent, theimprovement that comprises the concurrent administration of a selegilinecompound in an amount sufficient to permit the individual or cumulativedose of said agent to be maximized without unacceptably severeneurotoxic side effects.
 15. A method for treating a patient with cancerwhich comprises: a) administering to said patient a chemotherapeuticagent known to have a toxic effect on peripheral nerves, wherein saidchemotherapeutic agent is administered at a dose effective at slowingthe progression of said cancer; b) concurrently administering selegilineto said patient at a dose effective at reducing or eliminating theperipheral neuropathy associated with said chemotherapeutic agent; c)increasing the individual or cumulative dosage of chemotherapeutic agentuntil the peripheral neuropathy becomes unacceptably severe.
 16. Themethod of claim 15, wherein said patient is a human.
 17. The method ofclaim 15, wherein said chemotherapeutic agent is selected from the groupconsisting of cisplatin, paclitaxel, vincristine and vinblastin.
 18. Themethod of claim 15, wherein said selegiline is administered by a routethat avoids absorption of selegiline from the gastrointestinal tract.19. The method of claim 18, wherein said selegiline is administeredtransdermally, buccally or sublingually.
 20. The method of claim 18,wherein said selegiline is administered at a dose of between 0.01 mg/kgper day and 0.15 mg/kg per day.